Relationship between cerebral sigma-1 receptor occupancy and attenuation of cocaine's motor stimulatory effects in mice by PD144418

John R. Lever, Dennis K. Miller, Emily A. Fergason-Cantrell, Caroline L. Green, Lisa D. Watkinson, Terry L. Carmack, Susan Z. Lever

Research output: Contribution to journalArticlepeer-review


Psychostimulant effects of cocaine are mediated partly by agonist actions at sigma-1 (α1) receptors. Selective α1receptor antagonists attenuate these effects and provide a potential avenue for pharmacotherapy. However, the selective and high affinity α1antagonist PD144418 (1,2,3,6-tetrahydro-5-[3-(4- methylphenyl)-5-isoxazolyl]-1-propylpyridine) has been reported not to inhibit cocaine-induced hyperactivity. To address this apparent paradox, we evaluated aspects of PD144418 binding in vitro, investigated α1receptor and dopamine transporter (DAT) occupancy in vivo, and re-examined effects on locomotor activity. PD144418 displayed high affinity for α1sites (Ki0.46 nM) and 3596-fold selectivity over α2sites (Ki1654 nM) in guinea pig brain membranes. No appreciable affinity was noted for serotonin and norepinephrine transporters (Ki>100 μM), and the DAT interaction was weak (Ki9.0 μM). In vivo, PD144418 bound to central and peripheral α1sites in mouse, with an ED50of 0.22 μmol/kg in whole brain. No DAT occupancy by PD144418 (10.0 μmol/kg) or possible metabolites were observed. At doses that did not affect basal locomotor activity, PD144418 (1, 3.16, and 10 μmol/kg) attenuated cocaine-induced hyperactivity in a dosedependent manner in mice. There was good correlation (r2= 0.88) of hyperactivity reduction with increasing cerebral α1receptor occupancy. The behavioral ED50of 0.79 μmol/kg corresponded to 80% occupancy. Significant αc1receptor occupancy and the ability to mitigate cocaine's motor stimulatory effects were observed for 16 hours after a single 10.0 μmol/kg dose of PD144418. U.S. Government work not protected by U.S. copyright.

Original languageEnglish (US)
Pages (from-to)153-163
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - Oct 1 2014
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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